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Wednesday, 4 October 2017

Number of stool specimens

Several studies have now examined the influence of the number of samples used for testing on clinical
sensitivity and specificity. Allison takes any positive result from 3 stool samples measured using
FlexSure OBT as an indication for referral and shows higher sensitivity for cancer than studies using single stool samples (Allison et al. 2007). Unsurprisingly other studies show agreement with that
conclusion (St John et al. 1993; Allison et al. 1996; Knaani & Samuel 1997; Nakama et al. 1999;
Greenberg et al. 2000; Nakama, Zhang & Fattah 2000; Rozen, Wong et al. 2003). Nakama et al. using
Monohaem, showed sensitivities of 89% for cancer with 3 stools compared with 56% for a single stool
(Nakama et al. 1999).

Using Hem-SP, Morikawa showed low sensitivity for cancer using a single-day sample (Morikawa et al.
2005). Rozen et al. (2006) used 3 stools for the OC-Sensor which contrasts with 2-day samples used
in Japan (Nakama, Zhang & Fattah 2000) and 1-day biennial testing performed in Italy (Castiglione et
al. 2002). The relative insensitivity in the Italian study to lesions in the proximal bowel (16.3 vs
30.7%) raises further doubts about the use of a single-day sample. In a study using OC-Sensor in an
at-risk population, Levi et al. (2007) took numeric measurements from three samples and used the
highest concentration of the three as the discriminating factor. Recent studies have taken the average
concentration from 2 stool measurements as the discriminating parameter, an approach that reduces
the positivity rate.

The use of different cut-off limits and different numbers of stool samples illustrates how programme
algorithms can manipulate clinical sensitivities and specificities for the lesions of interest. Chen
describes the use of a cost-effectiveness model as a method of determining the optimal cut-off
concentration for an iFOBT (Chen et al. 2007). In the study by Levi et al. (2007) using an iFOBT OCMicro,
a scatter plot of 2 consecutive samples showed that of those with cancer or adenomas, 21 of
91 had elevated or markedly elevated faecal blood in one sample but were normal in the other. This is
further evidence of intermittent or variable bleeding, sample heterogeneity or poor sample technique
that will reduce clinical sensitivity. Imperiale (2007) commenting on the paper by Levi in his editorial
in Annals of Internal Medicine (Levi et al. 2007), speculated that concentration-related clinical
sensitivity and specificity could be used to determine post-test risk. If risk was related to subject age
or sex, this would provide more sophisticated criteria for colonoscopy referral than is currently used.

Guittet et al. (2009b), using a cut-off concentration of 20 ng/mL, reviewed the relative effectiveness
of using one sample, one positive from two samples, two positives from two samples or a mean
positive from two samples all measured using the Magstream iFOBT. The study concluded that for any
sensitivity the mean of two results provided the highest specificity, and at any positivity it provided
the highest sensitivity and specificity. It also concluded that one positive from a single specimen was
better than one from two specimens and the cut-off should be adjusted to provide an acceptable
positivity rate.

A recent paper by Grazzini et al. (2009) looks at the clinical outcome of biennial population screening
in 20 596 residents of Northern and Central Italy aged 50–69 years. The study uses OC-Sensor and
compares outcomes from strategies using different cut-off limits (80, 100 and 120 ng/mL), one or two
samples and referral criteria based on either one positive or two positive results. No strategy is singled
out as preferable, although some show limited benefit. Generally, those strategies resulting in more
colonoscopy referrals increase the detection rate, particularly for adenomas, decrease the positive
predictive value and cost more. At the annual Digestive Diseases Week conference in 2010 van Roon
et al. (2010) illustrated the relationship between positivity rate, detection rate, cut-off limits, the
number of samples measured and the use of different algorithms for combining the results. For
positivity rates between 4% and 9% the user can obtain similar clinical outcomes by changing the cutoff
with either one or two samples. The dilemma for a population-screening programme is where to
draw the line between detection rates, cost and the inconvenience and morbidity associated with
colonoscopy. The study showed no significant reduction in uptake for the two-sample strategy, but it
did require the samples to be stored in a refrigerator. The choice is likely to be influenced greatly by
both financial and logistical considerations.